As an approach to eludicating the genetic defect in cystic fibrosis (CF), an investigation has been continued on reported differences in plasma alpha2macroglobulin (alpha2M) from CF patients and normal individuals. The reportedly lower trypsin inhibitory activity in CF alpha2M could not be confirmed. However, a reported lower digestibility of CFalpha2M by trypsin, is in evidence. Also confirmed is a lower sialic acid content in alpha2M. On the other hand, it is found that enzymatic removal of the sialic acid content from normal alpha2M does not result in the observed differences in its interaction with trypsin, and hence factors other than the amount of incorporated sialic acid are responsible for the observed differences. One such factor may be the locations of the sialic acid residues within the protein, as is suggested by differences in the extent of removal of sialic acid with neuraminadase digestion. Thus, the reaction is approximately 90% complete for the normal protein but only 60-70% complete for the CF protein. Work continues on the investigation of sialic acid content as a possible source of observed differences between normal and CF alpha2M.